ZH-853

µ-Opioid receptor agonists, the gold standard for analgesia, come with significant side effects when used chronically. Tolerance, defined as the decrease in analgesic activity after repeated use, remains a vital therapeutic obstacle as it increases the likelihood of dose escalation and potentially lethal side effects like respiratory depression. Previous experiments have shown that the endomorphin-1 analog, ZH853, is a specific µ-opioid receptor agonist with reduced side effects like tolerance and glial activation following chronic central administration in pain-naive animals. Here, we investigated the effects of chronic, peripheral administration of µ-opioid receptor agonists following neuropathic injury. Though µ-opioids are effective at reducing neuropathic pain, they are not recommended for first-line treatment due to negative side effects. Compared with chronic morphine, chronic ZH853 treatment led to decreased tolerance and reduced glial activation. Following twice-daily intravenous injections, morphine was less potent and had a shorter duration of antinociception compared with ZH853. Chronic morphine, but not chronic ZH853, elevated markers of activation/inflammation of astrocytes (glial fibrillary acidic protein), microglia (ionized calcium-binding adapter molecule 1), the proinflammatory cytokine tumor necrosis factor-α, and phosphorylated mitogen-activated protein (MAP) kinase p38 (pp38). By contrast, chronic ZH853 reduced ionized calcium-binding adapter molecule 1 and tumor necrosis factor-α relative to both morphine and vehicle, suggesting anti-inflammatory properties with respect to these markers. Glial fibrillary acidic protein and pp38 were not significantly different from vehicle but were significantly lower than morphine. This study demonstrates the effectiveness of chronic ZH853 for providing analgesia in a neuropathic pain state with reduced tolerance compared with morphine, potentially due to reductions in spinal glial activation. PERSPECTIVE: Neuropathic pain is generally undertreated and resistant to medication, and side-effects limit opioid treatment. Here, we show that, compared with an equiantinociceptive dose of morphine, chronic intravenous administration of endomorphin analog ZH853 led to prolonged antiallodynia, reduced tolerance, and inhibition of spinal cord neuroinflammation in male spared nerve-injured rats.

Increasing evidence supported that oxidative stress induced by herniated lumbar disc played important role in the formation of lumbar disc herniation sciatica (LDHS), however, the neural mechanisms underlying LDHS need further clarification. Endomorphin-2 (EM2) is the endogenous ligand for mu-opioid receptor (MOR), and there is increasing evidence implicating the involvement of spinal EM2 in neuropathic pain. In this study, using an nucleus pulposus implantation induced LDHS rat model that displayed obvious mechanical allodynia, it was found that the expression of EM2 in dorsal root ganglion (DRG) and spinal cord was significantly decreased. It was further found that oxidative stress in DRG and spinal cord was significantly increased in LDHS rats, and the reduction of EM2 in DRG and spinal cord was determined by oxidative stress dominated increment of dipeptidylpeptidase IV activity. A systemic treatment with antioxidant could prevent the forming of mechanical allodynia in LDHS rats. In addition, MOR expression in DRG and spinal cord remained unchanged in LDHS rats. Intrathecal injection of MOR antagonist promoted pain behavior in LDHS rats, and the analgesic effect of intrathecal injection of EM2 was stronger than that of endomorphin-1 and morphine. Taken together, our findings suggest that oxidative stress mediated decrement of EM2 in DRG and spinal cord causes the loss of endogenous analgesic effects and enhances the pain sensation of LDHS.